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HIV Researchers Seek a Potential Cure

HIV research has reached the point that a cure may be possible. “HIV is a complicated disease, and it’s very encouraging to see advancements,” says Elizabeth Wolffe, Ph.D., Sangamo BioSciences spokesperson. “We’ve seen antiretroviral therapies that have made HIV a chronic disease. Now we’re starting to envision strategies to arm the body’s immune system to fight the virus. The industry is beginning to embrace the idea of cure strategies.”

Frost & Sullivan predicts a compound annual growth rate (CAGR) of 7.5% between 2012 and 2019, with 2012 sales estimated at $5.58 billion for Europe. Globally, BCC Research predicts market growth for HIV therapeutics at 4.6%. It projects global sales of $14.1 billion in 2016. Branded HIV products were expected to account for $13.2 billion of that. Generics, particularly in the developing world, make up the difference and are projected to grow commensurately.

Research got a boost in June when researchers at the NIH discovered how HIV attacks immune cells. Scientists saw that the DNA breaks that occur when HIV integrates its genes into cellular DNA activate DNA-protein kinase, triggering CD4+ T-cell death. This finding suggests that early, even prophylactic, treatment of individuals with drugs that block viral replication may not only prevent viral replication but also improve immune system function.

Sangamo BioSciences is using another approach to improve immune function with the ultimate aim of providing a functional cure. “HIV kills the CD4+ T cells such that the immune system seems never to regain control unless there is a delta 32 mutation in the CCR5 gene (which encodes the major co-receptor for HIV entry into CD4+ cells),” Dr. Wolffe explains.

“If the mutation is in both CCR5 genes, people can be exposed but not infected. If the mutation is in only one of the CCR5 genes, progression slows, giving rise to long-term nonprogressors.” The reason, she says, is that the R5-tropic strain (which is the most common strain at the early stages of infection) needs both CCR5 and CD4 to infect the cells.

Sangamo’s zinc finger protein (ZFP) technology, when attached to a nuclease or DNA-cutting enzyme, creates a new “designer” molecule—ZFN—that enables specific genes to be knocked out or have their expression disrupted. In repairing the break caused by the cutting enzyme, the cells often insert an error that makes the genes nonfunctional.

Sangamo is evaluating ZFP technology in two Phase II studies. Sangamo takes T cells from an HIV-infected individual treated with ART, treats the cells to disrupt the CCR5 gene, and about a month later, infuses the cells (SB-728-T) back into the patient, providing a population of T cells that is resistant to HIV and that also can mount an immune response against HIV and other opportunistic infections.

“We’ve had encouraging results,” Dr. Wolffe says. “The HIV-resistant T cells seem to traffic, moving throughout the body. They have been found in the gut tissues as well as the bloodstream.” Increasing levels of CD4 cells also were found in all patients. “Although the virus returns as patients are taken off ART, viral load decreases have been observed in several patients, with two reaching a transiently undetectable viral load."

Antiretroviral Therapy

Antiretroviral therapy (ART) is the current treatment class of choice. Although therapies in the ART class suppress viral load in most subjects, a significant proportion of these therapies do not restore normal CD4 counts. None address the viral reservoirs within the body.

Nonetheless, some very potent drugs have become mainstream. “These ARTs are very helpful in mother-to-child transmission and for accidental exposures,” observes Leo Stamatatos, Ph.D, scientific co-director, Seattle BioMed. “In the past few years, there’s been some thought of using these drugs prophylactically. In some cases, they have been successful, but adherence is a problem. People feel healthy, so they don’t take the drugs,” Dr. Stamatatos explains. ARTs taken long-term also cause serious complications of the liver, heart, and other systems.

New types of ART are gaining popularity. The Frost & Sullivan report, “Analysis of the European HIV Drugs Market,” specifically mentions pharmacokinetic boosters, maturation inhibitors, and attachment inhibitors. “Strong pipeline candidates under the integrase inhibitor drug class are expected to spur market expansion,” the report notes. That class of drugs is projected to increase the growth of the market because of “technically advanced features like easy consumption” that increase patient adherence to combination therapies.

In August, GlaxoSmithKline’s subsidiary ViiV Healthcare gained approval for Tivicay® (dolutegravir). This integrase strand transfer inhibitor (ISTI) interferes with one of the enzymes needed for HIV replication. The pill is taken once daily with other antiretroviral drugs and may be taken even by patients who have taken other ISTIs, as well as by treatment-naïve and experienced patients.

Gilead Sciences received European Union approval in May 2013 for Stribild® FDC, a single-tablet, fixed-dose-formulation, combination therapeutic. The company has submitted marketing approval applications for the PK booster cobicistat and for the ISTI elvitegravir in the United States and the European Union. Late-stage studies are ongoing for two co-formulations involving the nucleotide tenofovir alafenamide.

CytoDyn has two cell-specific monoclonal antibodies as product candidates for HIV infections. PRO 140 is an example of a new class of drugs, called viral entry inhibitors. Originally developed by Progenics Pharmaceuticals, this human monoclonal antibody prevents HIV from entering a cell by binding to CCR5, a primary receptor for HIV. Importantly, “It has not blocked the normal function of CCR5 in past studies. It received fast-track status from the FDA in 2006 and has completed Phase IIa studies. Phase IIb testing is scheduled to begin later this year,” John Procter, a spokesman for CytoDyn, reports.

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According to OyaGen, one of its investigational HIV drugs is an activator of the editing enzyme known as A3G, which can reportedly block HIV infection by genetically damaging the virus. HIV wages war on A3G at two times during an infection. (1) Early block: HIV infection induces A3G inactivation through complex formation with host cell RNAs. (2) Late block: Vif is expressed and Vif dimers bind to A3G to direct its destruction before A3G can be packaged with virions.

While PRO 140 is CytoDyn’s top development priority, the company also has another product candidate. Cytolin® originally was designed as a murine monoclonal antibody to identify cytotoxic T cells. The company developed a humanized version in 2011. It binds to the cellular antigen CD11a. Unlike other CD11a-specific antibodies, however, it does not block that cell’s normal function.

Merck has several compounds in Phase I and II development. According to clinicaltrials.gov, Merck is still recruiting for dose-ranging studies for MK-1439, doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI) in Phase II trials. A Phase I study is under way for EFdA, an NNRTI that has shown antiviral activity toward highly resistant HIV strains during preclinical studies.

OyaGen has two lead HIV drugs in preclinical development based upon editing enzymes. As Harold C. Smith, Ph.D., CEO, CSO, and founder, explains, “One is an activator of the editing enzyme known as APOBEC3G (A3G) that can block HIV infection by genetically damaging the virus (A3G Activator). The second is an antagonist of the viral protein known as Vif [viral infectivity factor] that HIV uses to trick cells into destroying A3G (Vif Antagonist).” This natural host defense system holds promise in bringing about a catastrophic failure of the viral genetic code that is essential for a functional cure for HIV.

Stem Cell Therapy

The so-called Berlin patient spurred research into stem cell therapy as a potential cure for HIV. That patient had been treated with ART, developed cancer, received a bone marrow transplant, and has been termed HIV-free. Since then, Timothy Henrich, M.D., of Harvard Medical School and Brigham and Women’s Hospital in Boston has used stem cell transplants to successfully treat two HIV patients. Both patients had been treated with antiretroviral therapy long-term before developing lymphoma.

“These findings might well alter the current thinking about HIV and gene therapy,” Kevin Robert Frost, CEO, amfAR, the Foundation for AIDS Research, said in a statement. “While stem cell transplantation is not a viable option for people with HIV on a broad scale because of its costs and complexity, these new cases could lead us to new approaches to treating, and ultimately even eradicating, HIV.”

Sangamo is engaged in early stage work with the California Institute for Regenerative Medicine through a $14.5 million grant to use zinc finger nucleases to modify hematopoietic stem cells, and thereby modify all the different cells of the immune system. “Our goal is to file an IND in 2014,” Dr. Wolffe explains.

Vaccines

Vaccines haven’t proven effective so far, but research continues. “There have been many proposals and many trials, but only the RV144 trial—known as the Thai trial—showed protection,” Dr. Stamatatos says. “HIV is a very diverse virus, so it’s hard to find a vaccine effective against all its variants.”

Academic institutes, including Seattle BioMed, are developing vaccines that will elicit antibodies against conserved sites among all HIV variants. Dr. Stamatatos says four conserved regions have been identified. “Ideally, we want to elicit antibodies against all four.” How, exactly, remains the question. Seattle BioMed and Scripps Research Institute have new leads. Dr. Stamatatos says corporate involvement is necessary to rapidly test these new vaccines.

Most of the corporate work in vaccines is being done by biotechs. The Esteve Group, GeneCure, Mymetics, TVAX Biomedical, United Biomedical, and others are each developing various HIV vaccines.

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